Parvalbumin neuron diversity and plasticity in primary visual and prefrontal cortical areas

Parvalbumin interneurons (PVIs) are essential for regulating cortical network activity, playing key roles in both the primary visual cortex (V1) and in the prefrontal cortex (PFC). PVIs have been implicated in schizophrenia, bipolar disorder, autism, and major depression, with transcriptomic alterations more pronounced than in other neuron types. However, the relationship between these changes in PVIs and corresponding physiological or morphological alterations remains unclear. Assessing these relations is the primary goal of this application. This exploratory R21 proposal investigates, using patch-seq, the properties of PVI subtypes and the effects of social isolation (SI), which induces PVI transcriptome changes in a manner relevant to psychiatric disorders. We will test whether region-specific PVI properties in mouse PFC and V1 contribute to the changes produced by SI. Our pilot studies revealed distinct electrophysiological subtypes of PVIs (continuous firing [cFS] and delayed fast-spiking [dFS]), in PFC and V1, as well as differences in axonal morphology. These baseline differences may contribute to region-specific PVI vulnerability to psychiatric disease or related manipulations. Aim 1 will establish the baseline transcriptomic signatures of PVI subtypes in PFC and V1 under standard group-housed conditions. Using patch-seq, we will integrate single-cell RNA sequencing, electrophysiology, and morphology to define the transcriptional markers distinguishing cFS and dFS subtypes in each region. Aim 2 will determine how SI alters PVI subtypes in PFC and V1 using patch-seq to assess changes in gene expression, excitability, and morphology. By correlating transcriptional changes with cellular phenotypes in the same neurons, this aim will reveal whether region-specific PVI properties shape differential responses to SI. This study is innovative in applying patch-seq to link transcriptional changes to multimodal cellular phenotypes in PVIs. It represents the first investigation of how experimental manipulations affect PVI subtypes across cortical regions. Our findings will provide crucial insights into region-specific PVI dysfunction and generate testable hypotheses on how molecular alterations contribute to disease-relevant cortical circuit changes. Project Number: 1R21MH142912-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Guillermo Gonzalez-Burgos | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $437,250 | Activity Code: R21 | Study Section: Pathophysiological Basis of Mental Disorders and Addictions Study Section[PMDA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11284940